PROJECT SUMMARY Alzheimer?s disease (AD), which consumed ~$226 billion in health care costs in 2015, is associated with nervous system chronic inflammation. Recent research revealed that the malfunction of microglia is critical for the development of AD. Our preliminary study developed a dual targeted dual responsive nanoparticle (DTDRN) which can effectively penetrate the blood brain barrier (BBB) and release its payload in the brain. Furthermore, N-acetyl cysteine (NAC)-loaded DTDRN showed much better therapeutic effect than free NAC in a LPS-induced brain inflammatory animal model. The objective of this study is to develop a brain targeted system for AD therapy by rationally utilizing the characteristics of both BBB and the brain tissue. In Aim 1, we will develop a NAC-DTDRN and characterize its BBB penetration efficiency in vitro. Aim 2 will evaluate the anti-inflammatory and anti-oxidant effects of the NAC-DTDRN in vitro and study its pharmacokinetics in vivo. Aim 3 will test the efficiency of the NAC-DTDRN in an AD animal model and evaluate its toxicity. In summary, NAC delivery via the proposed DTDRN system which can effectively penetrate the BBB and exhibit anti- inflammatory effects has potential to benefit AD patients. Due to the versatility of DTDRN, the proposed DTDRN system can carry other therapeutic molecules (both hydrophobic and hydrophilic) to the brain and to be applied for the detection and treatment of other central nervous system diseases such as Parkinson disease, traumatic brain injury, and multiple sclerosis.